The administration of a drug through the skin for systemic distribution, that is transdermally, can provide compelling advantages relative to other modes of administration. Transdermal administration circumvents potential complications in the gastrointestinal (“GI”) tract, avoids first-pass metabolism in the liver, can allow delivery of an active ingredient with a relatively short biological half-life or a narrow therapeutic window, facilitates uniform plasma dosing of the active ingredient, and, as above, is broadly preferred from a user compliance perspective.
In spite of the advantages, transdermal administration is limited to only a small number of drugs. For example, a transdermal patch format is currently limited to some thirty drugs (including scopolamine, fentanyl, estradiol, nitroglycerin, nicotine, testosterone, selegiline and methyl phenidate). The reason for the paucity of transdermal products to treat serious pain conditions is that the skin presents a formidable barrier.
Structurally, the skin consists of two principle layers: (i) the epidermis, the outermost layer, which varies in thickness from 0.05 mm on the eyelids to 1.5 mm on the palms and soles of the feet but which typically averages 80 μm, and (ii) the ‘dermis,’ the inner region, ranges in thickness from 0.4 to 4 mm, with a typical average of 2 mm. The outermost layer of the epidermis (the ‘stratum corneum’) comprises corneocytes (flattened dead cells which are filled with keratin), interconnected by corneodesmosomes and surrounded by lipids which form lamellar phases. The highly impermeable nature of skin is due primarily to the stratum corneum. The viable epidermis underlying the stratum corneum is akin to other living tissue. The dermis provides the skin's structural strength as well as the nerve and vascular networks that support the epidermis.
Various factors can affect the skin absorption rates and penetration depths of a drug molecule applied in a formulation to the skin, including the nature of the active ingredient, the nature of the vehicle, the pH, and the relative solubility of the active in the vehicle versus the skin. More specifically, drug attributes such as solubility, size and charge, melting point as well as vehicle attributes such as the drug solubility and dissolution rate, ability to alter the membrane permeability, spreadability and adhesion can each have significant effects on permeability.
Delivering an active agent into or through the skin in sufficient concentrations usually requires some means for reducing the stratum corneum's hindrance to ingress of the active agent. A number of physical methods for lowering the stratum corneum's barrier properties have been developed including electrically assisted techniques such as iontophoresis or electroporation, ultrasound, heat, puncturing the stratum corneum with microneedle arrays, or ablation. Even for a single, non-repeated application such physical methods have limitations, leading to very restricted use by patients in practice.